CN115028625A - 一类β-咔啉喹啉杂合物、制备方法与应用 - Google Patents
一类β-咔啉喹啉杂合物、制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，具体涉及一类β‑咔啉喹啉杂合物、制备方法与应用，β‑咔啉喹啉杂合物具有通式Ⅰ所示结构：
该β‑咔啉喹啉杂合物可在酸性pH下激活，利用ICT原理产生近红外荧光，可应用在肿瘤组织酸性微环境，选择性地在肿瘤部位快速产生pH敏感的近红外荧光，将本发明β‑咔啉喹啉杂合物的溶液喷洒或局部注射于肿瘤病灶部位及周围的组织上，利用荧光腔镜或活体成像仪对肿瘤病灶组织进行快速、选择性荧光成像和示踪，具有较高的肿瘤组织荧光成像选择性和较低的背景荧光干扰。
Description
技术领域
本发明涉及生物医药领域，涉及一类β-咔啉喹啉杂合物、制备方法与应用，具体涉及一类pH敏感的近红外成像的β-咔啉喹啉杂合物荧光探针及其制备方法与应用。
背景技术
目前，癌症是目前对人类健康的最大威胁之一。到2035年，世界卫生组织估计每年可能有2400万新病例和1450万与肿瘤相关的死亡。早期诊断和治疗可以挽救大约30％的癌症相关死亡。
荧光探针技术以其独特的高灵敏度、高选择性、原位和实时检测、高时空分辨率和非侵入性等优势，已成为实现体内酶活性选择性成像的有力手段，已经普遍应用于癌症的准确诊断、治疗和相应的药物治疗评价。然而，由于组织中强烈的本征光散射，在活体成像中，随着深度的增加，空间分辨率和穿透能力会迅速降低。近红外(NIR)双光子(TP)荧光成像是一种很有前途的酶活性活体成像工具，具有自发荧光减弱、组织穿透性和分辨率高等优点。再者，目前大多数小分子荧光探针仅能够单光子激发，与这些荧光探针相比，研究开发具有双光子激发特性的荧光探针能够对组织产生更深的穿透能力，扩大激发和发射波长差值，可有效避免组织自身荧光和光源背景的干扰，同时双光子激发波长对组织的损伤较小。
近年来，一系列酶激活的荧光探针被开发出来并应用于肿瘤的诊断和治疗中，它们对过表达的氨肽酶、α-谷氨酰转肽酶、β-半乳糖苷酶、碱性磷酸酶等有反应，遗憾的是，由于不同癌细胞中酶的表达水平不同，应用它们快速显示广泛的恶性肿瘤的可行性尚不可能。相比之下，pH失调是一个典型的癌症标志，不论癌症类型，由于有氧糖酵解，癌细胞优先转化葡萄糖为乳酸。已有文献报道通过控制pH敏感键的断裂来控制荧光，但大都基于腙键、亚胺键或缩醛等，不具备荧光可逆性且无法实现对肿瘤进行实时、精确、快速地成像诊断。
发明内容
针对以上问题，本发明对β-咔啉进行修饰改造，提供了一类β-咔啉喹啉杂合物、制备方法与应用，该β-咔啉喹啉杂合物为pH敏感的近红外成像的β-咔啉喹啉杂合物荧光探针，通过单光子和/或双光子激发、酸性pH刺激响应，可应用于进行体内外肿瘤选择性荧光成像试剂制备的医药用途，以引导手术切除和/或药物治疗，进而对于癌症的快速诊断和治疗具有重要应用意义。
为了实现上述目的，本发明采用的技术方案如下：
一类β-咔啉喹啉杂合物，具有通式Ⅰ所示结构：
其中，β-咔啉喹啉杂合物为pH敏感、近红外成像的β-咔啉喹啉杂合物荧光探针，R选自H或NH2。
上述通式Ⅰ部分化合物代号及其对应的化合物名称如下：
I1:(E)-1,9-二甲基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚；
I2:(E)-1,9-二甲基-6-氨基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚。
本发明还提供了化合物I1的制备方法：
本发明的另一目的在于提供本发明通式Ⅰ所述化合物的如下制备方法：将1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛(1)与4-甲基喹啉(2)在催化量哌啶条件下，加热回流，发生Knoevenagel缩合反应获得化合物I1；
合成路线如下所示：
本发明还提供了化合物I2的制备方法，具体为：将1,9-二甲基-6-硝基-9H-吡啶并[3,4-b]吲哚-3-甲醛(3)与4-甲基喹啉(2)在催化量哌啶条件下，加热回流，发生Knoevenagel缩合反应获得化合物4；化合物4在还原剂铁粉和氯化铵的乙醇溶剂下，加热回流，经还原反应获得化合物I2；
合成路线如下所示：
本发明还提供了上述β-咔啉喹啉杂合物在制备通过单光子和/或双光子激发的荧光成像试剂中的应用。
进一步的，所述荧光成像试剂为用于体内外肿瘤组织或肿瘤细胞的选择性荧光成像试剂；优选的，该荧光成像试剂为荧光显影剂。
进一步的，所述荧光成像试剂为通过喷洒或局部注射的方式实现肿瘤的快速、实时检测和成像的试剂。
进一步的，荧光成像试剂由β-咔啉喹啉杂合物溶于助溶剂/表面活性剂/溶剂体系得到；所述助溶剂/表面活性剂/溶剂体系中，助溶剂为1,2丙二醇、DMSO和乙醇中的一种或几种；溶剂为水；表面活性剂为吐温20、吐温40和吐温80中的一种或几种。
进一步的，所述助溶剂/表面活性剂/溶剂体系中，按体积百分比计，所述助溶剂的含量为1～30％，所述表面活性剂的含量为1～30％。
进一步的，所述肿瘤为肝癌、结肠癌、乳腺癌、肺癌和宫颈癌肿瘤中的一种。
与现有技术相比，本发明具有的应用效果：本发明专利公开了一类非季铵盐形式的β-咔啉喹啉杂合物，不同于以往的季铵盐型β-咔啉喹啉鎓盐类化合物(在激发光下一直亮着，无酸性pH激活响应性荧光，不能发挥“开-关”效应荧光，从而无肿瘤选择性荧光成像)，而本发明化合物能够在酸性pH下激活，利用ICT原理产生近红外荧光，可应用在肿瘤组织及其酸性微环境，获得肿瘤组织和细胞选择性的荧光成像。具体实施方法是将喷洒或局部注射本发明化合物溶液于术前或术中肿瘤病灶部位及周围的组织上，利用荧光腔镜或活体成像仪对肿瘤病灶组织进行快速、选择性荧光成像和示踪，具有较高的肿瘤组织荧光成像选择性和较低的背景荧光干扰，能够对肿瘤进行精确诊断，以指导手术和/或药物治疗。
附图说明
图1是本发明化合物I2不同pH的紫外吸收光谱图，横坐标为波长，纵坐标为吸光度值；
图2是本发明化合物I2不同pH的荧光发射光谱图，横坐标为波长，纵坐标为荧光强度；
图3是本发明荧光探针部分化合物的双光子吸收截面图；
图4是本发明荧光探针部分化合物实现体内外肿瘤细胞的选择性荧光成像的应用示意图；
图5是本发明荧光探针部分化合物对离体肿瘤组织选择性荧光成像试验示意图。
具体实施方式
下面结合附图将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：(E)-1,9-二甲基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚(I1)的制备
将1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛(500mg,1.0mmol)和4-甲基喹啉(320mg，1.0mmol)加入单口瓶中，用无水乙醇(10ml)溶解，随后加入1-2滴哌啶，85℃回流12h，经TLC监测反应结束后，抽滤，再次重结晶纯化得到化合物I1，产率为86％.
化合物I1的谱图数据为：1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝6.8Hz,1H,ArH),8.89(s,1H,ArH),8.73–8.65(m,2H,ArH),8.48(d,J＝7.8Hz,1H,ArH),8.41(d,J＝15.6Hz,1H,CH),8.27–8.34(m,2H,ArH),8.15(d,J＝8.4Hz,1H,ArH),8.02(m,1H,ArH),7.85(s,1H,CH),7.72(m,1H,CH),3.41(s,3H,CH3),1.37(s,3H,CH3).
实施例2：(E)-1,9-二甲基-6-氨基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚(I2)的制备
参照实施例1中(I1)的合成方法，由1,9-二甲基-6-硝基-9H-吡啶并[3,4-b]吲哚-3-甲醛代替方法中的1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛，最后得到化合物4；再将化合物4(500mg,1.0mmol)、铁粉(274mg,4.0mmol)、氯化铵(523mg,8.0mmol)加入单口瓶中，用无水乙醇(20ml)溶解，80℃回流5h，经TLC监测反应结束后，抽滤，将滤液旋干，经柱层析纯化，得到化合物I2，产率为73％。
化合物I2的谱图数据为：9.11(d,J＝6.8Hz,1H,ArH),8.94(d,J＝8.1Hz,1H,ArH),8.63(m,1H,ArH),8.45(m,2H,2ArH),8.32(d,J＝15.6Hz,1H,CH),8.11(m,1H,ArH),7.98(s,1H,ArH),7.71(m,1H,ArH),7.48(d,J＝15.6Hz,1H,CH),4.42(s,2H,NH2),3.40(s,3H,CH3),3.35(s,3H,CH3).
实施例3：本发明不同pH条件下荧光探针的紫外吸收光谱测试
将本发明实施例2得到的化合物I2溶于含50％的乙醇水溶液中，配制成pH＝3-8，浓度为20μM的检测液。采用紫外-可见分光光度计测试其紫外吸收光谱数据，结果如图1所示，图1显示，本发明化合物I2紫外最大吸收波长在450-600nm范围内，在415nm左右的紫外吸收峰值随化合物I2的pH减小而减小，相反其在532nm左右的紫外吸收峰值随pH减小而增加，其峰值相差57倍。
实施例4：本发明实施例2制备得到的化合物I2的pH响应的荧光光谱测试
将本发明实施例2制备得到的化合物I2溶于含50％的乙醇水溶液中，配制成pH＝3-8的检测液。采用荧光光谱仪测试其荧光发射光谱数据，结果如图2所示，图2显示，本发明化合物I2最大发射波长在650-750nm范围内，在691nm左右的荧光峰值随化合物I2的pH减小而增加，相反其荧光峰值随pH增加而减小，其峰值相差12倍。
实施例5：采用飞秒荧光测量技术检测不同波长下的双光子吸收截面
将本发明化合物I2溶于pH＝4.0的PBS缓冲液中(5μM)，检测本发明化合物和对照化合物Ru(bpy)3 2+从920nm到1100nm的双光子激发下的荧光强度。利用公式：δ＝δr×(Fs×фr×nr)/(Fr×фs×ns)，其中，δ，F,ф和n分别是双光子吸收截面，光谱积分面积，量子产率和浓度；s和r分别代表了本发明化合物和对照化合物。计算不同波长下该还原产物的双光子吸收截面，计算结果如图3所示，结果表明，本发明化合物I2在1000nm具有最大的双光子吸收截面(δmax＝116GM)。
实施例6：采用共聚焦显微镜进行细胞成像
参照图4，采用共聚焦显微镜进行肺癌细胞(A549)、正常胚肺成纤维细胞(HFL-1)或结肠癌细胞(HT29)荧光成像，放于激光共聚焦皿中培养24h，再向细胞中加入10μM的受试化合物，将其放置置于37度、含5％CO2的细胞培养箱中孵育半小时。接着用pH＝7.4的磷酸盐缓冲溶液洗涤3次后，将孵育好的细胞置于共聚焦显微镜的载物台上进行共聚焦荧光成像，设置受试化合物激发波长：λem＝450-600nm，λex＝650-750nm。
细胞成像结果表明，本发明化合物可以被肿瘤细胞有效吸收，表明该类荧光化合物可以对多个肿瘤细胞荧光成像，而对正常肺成纤维细胞荧光成像很弱，由此说明本发明化合物具有肿瘤细胞选择性荧光成像，为体内外肿瘤组织或细胞成像研究提供了一种可行的手段。
实施例7：本发明化合物对离体肿瘤组织进行喷洒模式的荧光成像试验
取Hela宫颈癌模型裸鼠，将其处死，取出宫颈肿瘤及主要脏器进行喷洒成像分析。将配制好的本发明化合物I1溶液50μM喷洒在组织上3～5次，用PBS清洗并用棉花吸干，荧光成像结果如图5所示，宫颈癌组织的荧光强度值明显高于其他正常器官组织，而正常器官组织荧光相对较弱。由此说明了本发明化合物可选择性、快速对肿瘤组织喷洒成像，以实现临床对肿瘤组织的快速检测。
以上对本发明的实施例进行了详细说明，但所述内容仅为本发明的较佳实施例，不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等，均应仍归属于本发明的专利涵盖范围之内。
Claims (9)
1.一类β-咔啉喹啉杂合物，其特征在于，所述β-咔啉喹啉杂合物具有如下通式所示结构：
所述β-咔啉喹啉杂合物为pH敏感、近红外成像的β-咔啉喹啉杂合物荧光探针，R选自H或NH2；
R＝H时，化合物I1为(E)-1,9-二甲基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚；
R＝NH2时，化合物I2为(E)-1,9-二甲基-6-氨基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚。
2.一种β-咔啉喹啉杂合物的制备方法，其特征在于，所述β-咔啉喹啉杂合物为(E)-1,9-二甲基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚，所述制备方法为：将1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛与4-甲基喹啉在催化量哌啶条件下，加热回流，发生Knoevenagel缩合反应获得所述β-咔啉喹啉杂合物；
所述制备方法的合成路线如下所示：
3.一种β-咔啉喹啉杂合物的制备方法，其特征在于，所述β-咔啉喹啉杂合物为(E)-1,9-二甲基-6-氨基-3-(2-(喹啉-4-基)乙烯基)-9H-吡啶并[3,4-b]吲哚，所述制备方法包括以下步骤：
S1.将1,9-二甲基-6-硝基-9H-吡啶并[3,4-b]吲哚-3-甲醛与4-甲基喹啉在催化量哌啶条件下，加热回流，发生Knoevenagel缩合反应获得化合物4；
S2.化合物4在还原剂铁粉和氯化铵的乙醇溶剂下，加热回流，经还原反应获得所述β-咔啉喹啉杂合物；
所述制备方法的合成路线如下所示：
4.权利要求1所述的β-咔啉喹啉杂合物在制备通过单光子和/或双光子激发的荧光成像试剂中的应用。
5.根据权利要求4所述的应用，所述荧光成像试剂为可实现肿瘤选择性荧光成像试剂，所述肿瘤为肿瘤组织或肿瘤细胞。
6.根据权利要求5所述的应用，其特征在于，所述荧光成像试剂为通过喷洒或局部注射的方式实现肿瘤的快速、实时检测和成像的试剂。
7.根据权利要求4所述的应用，其特征在于，所述荧光成像试剂由β-咔啉喹啉杂合物溶于助溶剂/表面活性剂/溶剂体系得到；所述助溶剂/表面活性剂/溶剂体系中，助溶剂为1,2丙二醇、DMSO和乙醇中的一种或几种；溶剂为水；表面活性剂为吐温20、吐温40和吐温80中的一种或几种。
8.根据权利要求7所述的应用，其特征在于，所述助溶剂/表面活性剂/溶剂体系中，按体积百分比计，助溶剂的含量为1～30％，表面活性剂的含量为1～30％。
9.根据权利要求5-8任一项所述的应用，其特征在于，所述肿瘤为结肠癌、肺癌、胰腺癌、乳腺癌、肝癌和宫颈癌肿瘤中的一种。
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